Targeted and Chemotherapy Treatment Options in ALL

Video

Transcript:Stefan Faderl, MD: The question is about induction of therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia, in particular the use of tyrosine kinase inhibitor therapy. Ever since imatinib went into clinical trials, and it became available, it was incorporated into chemotherapy backbones in the treatment of patients with acute lymphoblastic leukemia characterized by the Philadelphia translocation. And what it essentially showed that it’s: 1) doable in terms of the toxicity profile, and 2) that it is actually effective, not so much in increasing the initial response rate but, more importantly, increasing the odds and probabilities of maintaining a remission even outside the area of stem cell transplant.

Now, when the second generation of kinase inhibitors became available, in particular dasatinib or nilotinib, for instance, it was a similar discussion as in chronic myeloid leukemia, the idea that the more potent second-generation kinase inhibitor might be providing an even better benefit compared to imatinib. And lo and behold, the clinical trials were conducted. They essentially showed the same paradigm, if you will, that they can be combined safely with chemotherapy backbones, on the one hand, and that they are effective as well. As a matter of fact, at the last ASH meeting in 2015, results from a US InterGroup study were presented looking at the addition of dasatinib to intensive chemotherapy, and the response rates looked very well, 88% with a survival probability of one year of 88% as well.

If you ask the question: which one is better now, imatinib or a second-generation kinase inhibitor, I think it’s a little bit hard to answer. And the answer is not quite clear to me, maybe because of a lack of randomized studies that really formally compare the experience, outcomes with an imatinib combination and a second-generation kinase inhibitor combination.

The more interesting question is whether, with the kinase inhibitors, you could minimize or eliminate chemotherapy altogether. And the answer may be yes, you may be able to do so. There are several studies that looked at that question as well. A more recent one, which was also part of the ASH presentation in 2015, is by the Italian GIMEMA group that looked at about 65 patients, I think, who were treated with a combination of steroids plus dasatinib for about three months. And patients were obviously evaluated as to their response and overall outcome. You actually can achieve very high hematologic response rates in the range of 95%-100% with even a complete molecular response right around 20% and 3-year overall survival rates of about 60%.

Now, the protocol was a little more complicated in that some patients who did not quite achieve certain levels of response won’t have the option to continue with chemotherapy and be eligible for stem cell transplant. But lo and behold, a lot of patients treated with kinase inhibitor plus steroids or minimal other type addition of chemotherapy drugs were able to achieve very high responses and maintain them. I think that’s quite promising for future design of other studies or treatments that a lot of the activity in those combinations seems to rely on the kinase inhibitor, maybe not so much on heavy chemotherapy backbone.

Philadelphia chromosome-like or BCR-ABL-like acute lymphoblastic leukemia is a more recently characterized subtype of acute lymphoblastic leukemia. It has the same gene expression profile as you would find in patients with truly Philadelphia-chromosome-positive acute lymphoblastic leukemia, but it lacks the Philadelphia translocation and by extension. It also lacks the BCR-ABL rearrangement. It has been clinically associated with higher white cell counts at presentation, male gender, less responsiveness to therapy, a higher incidence of persistence of minimal residual disease after therapy. And if you can put this all together, it’s been associated with a worse outcome compared to say non-BCR-ABL-like acute lymphoblastic leukemia.

The interesting part about the subtype is if you look a little bit closer at the molecular level, in a lot of those patients you identify actual molecular abnormalities that relate to cytokine receptors or actually kinase mutation functions. In about 50% of BCR-ABL-like ALL you find rearrangements of CRLF2, a particular gene. Half of those patients actually have JAK2 mutations. And if you look at the other 50%, you find a number of other kinase mutations affecting ABL1 kinases, JAK2 EPO receptor, for instance, or RAS-MAP kinase pathway mutations. The rearrangements are between ETV6, and ABL1 is one example of a chimeric tyrosine kinase affected in that context. It’s actually not that frequent in acute lymphoblastic leukemia and it also extends to myeloid leukemias. And the incidence in ALL is probably 0.5% or so. But it’s a nice example as what you can detect in a molecular level, and by extension, it’s important. It’s a targetable, actionable abnormality that may be responsive to kinase inhibitors such as dasatinib, imatinib but also others such ruxolitinib is a JAK2 inhibitor, for instance. It opens up the possibility for actually kinase inhibitor therapy in a substantial proportion of patients.

Bijal D. Shah, MD: Our approach to Philadelphia-negative B-cell ALL at the Moffitt Cancer Center has been to use the hyper-CVAD backbone. We have a lot of familiarity with this backbone and the ability to build on to this backbone is one of the things that I like most about it. I had mentioned previously that by using MRD, we can then best determine how to intensify therapy from that standpoint if we’re seeing something we don’t like. Whether those therapies will improve outcome, certainly that’s my hope. And so building things, as I mentioned, like allogeneic transplant or even asparaginase or other molecularly targeted therapies onto that hyper-CVAD backbone is something we have more familiarity with.

Rituxan is a perfect example of this. We now have prospective data to show Rituxan combined with chemotherapy will improve outcomes. We also have retrospective data with the hyper-CVAD regimen showing that Rituxan in the CD20-positive subset of patients with AP [accelerated phase] ALL will improve outcomes. It’s important to know that the EFS was significantly improved in this prospective trial presented here at ASH 2015. It was around a 20 month EFS, if I remember correctly. That’s a big deal. That’s a very big deal. There are big questions that we still need to sort out. What are they? 1) The maximum age on this study was 60. Will Rituxan benefit older patients with B-cell ALL? I think the answer is yes, but the problem right now that we’re running into is the toxicity of therapy is such that we’re not able to actually realize that endpoint. So can we start moving Rituxan forward in the context of lower intensity therapies and see an improvement in that space?

Transcript Edited for Clarity

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